My Medwatch report to the FDA:

Trazodone ==> mCPP may induce psychosis;
Trazodone should have a warning label

Submitted on December 30, 2002

- Bonze Anne Rose Blayk

(F/K/A "Kevin Eric Saunders a/k/a bonze blayk")

Kevin Eric Saunders a/k/a bonze blayk
Describe event or problem up to a total of 6400 characters allowed
NOTE... my GP is Dr. Breiman of Family Medicine Associates, 209 W. State
St., Ithaca, NY 14850. The psychiatrist who prescribed the drugs which
caused the adverse reactions was the (now-deceased) Dr. Robert Hamlisch.
If you would please provide me with an email contact address, I can also
submit research citations in RTF format which support this analysis.
SUMMARY: Concurrent use of fluoxetine (Prozac, 20mg/day in the morning
as an antidepressant) and Trazodone (50 mg/day at bedtime as a "sleep
aid") over 6 days led to peripheral numbness, heart palpitations, urinary
retention, visual distortions, and eventually paranoia and delusions.
Discontinuation of Trazodone after 6 days and later substitution of
Hydroxyzine Pamoate (25 mg) as a "sleep aid" further complicated the
adverse reaction, eventuating in frank psychosis with prominent auditory
hallucinations (2/5/97).
Fluoxetine was initiated 12/28/96, followed by Trazodone (taken at
bedtime) on 1/4/97.
On an ER visit on 1/11/97 physical symptoms listed above were dismissed
by the ER examiner as effects of "agitated depression." (Fluoxetine had
been used 8/96 - 10/96 at 10mg/day, but had been discontinued due to
mildly unpleasant side effects.)
I discontinued Trazodone, since according to the Trazodone insert it
might be a possible cause of the heart palpitations I had felt; on
1/16/97 Hydroxyzine Pamoate (Vistaril) was prescribed as an alternative
"sleep aid," resulting in extreme anticholinergic side effects and
worsening of paranoia.
I believed I was suffering from a serious neurological disorder, and
resumed smoking cannabis for about two weeks (through 1/28/97) in the
hope I would experience some relief of the symptoms. (NB: I had never
experienced any significant negative side affects from smoking marijuana
over 20 years of fairly regular use, which had been discontinued more
than one month prior to going on fluoxetine ... nor, prior to this
incident, psychosis from any cause.) Use of cannabis was discontinued in
the expectation that I would soon be undergoing an NCV test for the
presence of neurological problems (since use of cannabis could
conceivably be reducing inflammation or affecting other neuropathic
processes).
For some period during this interval, I completely lost all sensations of
appetite, and lost 20 pounds.
On 2/6/97 I suffered a major psychotic episode involving delusions and
auditory hallucinations.
Since the psychosis wound up resulting in serious criminal charges,
consequently resulting in an acquittal under New York State law as "Not
Responsible for Reason of Mental Disease or Defect," the cause of the
psychosis was considered by a number of psychiatrists, neurologists, and
psychologists. No signs of brain abnormalities were found in an MRI
(5/12/97). The possibility of a neurological disorder was dismissed
after subsequent 3-day sleep-deprived EEG testing showed no abnormalities
(2/98). The diagnosis of Cannabis-Induced Psychotic Disorder was also
considered and dismissed.
Psychiatric and psychological examiners made varying diagnoses, including
some questioning the presence of psychosis during the criminal offense
(particularly since I'd been consistently found to be rational in
numerous examinations). No doctor or other examiner ever considered the
possibility of side effects from Prozac, Trazodone, or Hydroxyzine as a
factor.
Around May 2000, I finally identified the underlying cause(s) of my
physical illness in January 1997 (and subsequent psychosis) when I found
research which identified both Fluoxetine and Trazodone as sodium channel
blockers capable of inducing paresthesias. My suspicions having been
heightened, I did more research on Trazodone, and discovered that
Trazodone has an anxiogenic byproduct with hallucinogenic properties:
the serotinergic agonist mCPP (meta-chlorophenylpiperazine). The
anxiogenic properties of mCPP are widely used in clinical research; the
hallucinogenic properties have gone largely unrecognized (though note
"The subjective effects of MDMA and mCPP in moderate MDMA users", Tancer
& Johanson, PMID 11714594, and reports of delirium induced by Trazodone
where these effects were probably caused by mCPP, e.g.,
"Trazodone-induced delirium in bulimic patients," Damlouji & Ferguson,
PMID 6584039).
Also, mCPP is a powerful anorectic agent, accounting for my loss of
appetite!
Moreover, I found that research has clearly established that Fluoxetine
impairs clearance of substances metabolized by the P450IID6 enzyme (and
indeed there is a warning noting this effect in the Prozac monograph)...
which includes mCPP, as well as Hydroxyzine. (It is not known whether I
have a defective allelle at CYPIID6 causing impaired P450IID6 metabolism
-- present in about 7.5% of the Caucasian population -- since I have been
unable to find a doctor or lab performing dextromethorphan/dextrorphan
ratio or other tests of P450IID6 functioning.)
Thus, the "rare" CNS side effects of paranoia, delusions, and
hallucinations listed in the Trazodone monograph are statistically
predictable disasters: Trazodone has tranquilizing, antipsychotic
properties which ordinarily mask the anxiogenic, psychotogenic properties
of mCPP... but the vagaries of metabolism may result in Trazodone
clearing relatively unimpaired P450IIIA4 channels while mCPP accumulates
as a result of P450IID6 blockade.
CONCLUSION: I strongly believe that the labelling of Trazodone (and,
likewise, of Serzone) should clearly indicate that it produces mCPP, a
panic-inducing hallucinogenic byproduct, and that clearance of this
byproduct may be impaired by use of other drugs or by genetic variations
affecting the P450IID6 enzyme.
6. Relevant tests/laboratory data, including dates
up to a total of 1000 characters allowed
Cayuga Medical Center: ER 1/11/97 for complaints of heart palpitations,
peripheral numbness, urinary retention, etc. No tests directly relevant
to the question of plasma levels of Fluoxetine, Trazodone, mCPP, or
Hydroxyzine Pamoate were performed. Other tests were normal (EKG, chest
X-ray, lab work).
Dr. Jody Stackman (neurologist): neurological exam 1/20/97, NCV
(negative) 3/26/97, MRI (negative) 4/8/97
Strong Memorial Hospital, Rochester: 2/11/98, 3-Day sleep-deprived EEG
(negative for epilepsy)
7. Other relevant history, including preexisting medical conditions,
(e.g. allergies, race, pregnancy, smoking and alcohol use, hepatic/renal
dysfunction, etc.) up to a total of 500 characters allowed
Discussed in Section B5.
1. Name
(Product Name) (Label Strength) (Mfr/Labeler)
#1 Trazodone 50mg
#2 Prozac 20mg Eli Lilly
2. Dose/Frequency/Route used
#1 50mg / nightly / op
#2 10mg / morning / op [sic 4/23/11: should be 20mg]
3. Therapy Dates (or best estimate)
If necessary, use Section B5 to explain or clarify dates.
From To
#1 1/4/97 - 1/10/97
#2 12/31/96 - 6/30/97
4. Diagnosis for use (separate indications with commas)
#1 Insomnia
#2 Depression
5. Event abated after use stopped or dose reduced
#1 Yes (No) Doesn't Apply
#2 Yes (No) Doesn't Apply
6. Lot # If known
#1
#2
7. Exp. Date If known.
If necessary, use Section B5 to explain or clarify dates.
#1
#2
8. Event reappeared after reintroduction
#1 Yes No (Doesn't Apply)
#2 Yes No (Doesn't Apply)
9. NDC #(for product problems only)
10. Concomitant medical products and therapy dates (exclude treatment of
event)
Vistaril 25mg / 1-2 prn for insomnia / 1/16/97 - ? precise dosages
unknown

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